The extracellular adenosine receptor has a modulatory role in the nervous, circulatory, endocrine, and immunological systems. The prospect of harnessing these effects specifically for therapeutic purposes is attractive. We have developed research tools for the characterization of adenosine receptors in vitro and in vivo. We have synthesized new drug analogues and elucidated structure activity relationships at receptor subtypes. Derivatives of adenosine with chemical modifications at the N6 and C-2 positions of the purine ring act as selective adenosine agonists. Al- agonists are being explored as cerebroprotective agents. To enhance brain uptake, prodrug schemes are being examined. APEC, and A2 selective adenosine amine congener served as the basis for a photoaffinity labeling reagent that allowed the first determination of the molecular weight of the receptor. Functionalized congeners of xanthines act as potent adenosine antagonists and are being developed as radioactive tracers for adenosine receptors and as affinity labels. Peripherally selective adenosine agonists have been developed. Since the two major subtypes of adenosine receptors have been cloned it has been possible to conduct molecular modeling of the receptor protein, based on sequence analyses and computerized energy minimizations. A hypothesis concerning the mode of binding to ligands to adenosine receptors has been derived. This hypothesis is consistent with pharmacological observations and site directed mutagenesis experiments, in which key histidyl residues have been replaced by other amino acids.